EVIDENCE FOR MULTIPLE GENES DETERMINING SODIUM-TRANSPORT

Sodium transport comprises a set of interacting systems. Consequently, a defective sodium transport gene affects multiple sodium transport s ystems, and a sodium transport variable measured on a sample of indivi duals reflects genetic variation from a number of different genes, com plicating the task of identifying the effect of a single gene. To test for genes which affect sodium transport, we first applied principal c omponents analysis to 14 variables related to sodium transport, thereb y defining uncorrelated sources of variation in the variables. The sam ple consisted of 1,218 members of 68 pedigrees ascertained through pro bands with early-onset stroke, hypertension, or coronary heart disease . Segregation analysis of the 14 principal components scores provided evidence for 8 genetic variants which alter sodium transport. One of t he 8 variants is recessive, has homozygous genotype frequency estimate d as 8.8% of the population, and increases sodium-lithium countertrans port, the passive sodium leak, body mass index, and triglyceride; the genetic variant may coincide with an insulin resistance gene. A second of the 8 variants is also recessive, has homozygous genotype frequenc y estimated as 7,4% of the population, and increases intraerythrocytic sodium and the passive sodium leak while decreasing sodium pump numbe r; the genetic variant may reduce pump number. Two Of the 8 variants s ubstantially increase sodium-lithium countertransport; frequency estim ates for heterozygotes for the dominant Variant and homozygotes for th e recessive variant equal 1.8% and 3.1%, respectively. Another of the 8 variants is recessive, has homozygous genotype frequency estimated a s 1.9%, and increases body mass index. Each of the 3 remaining variant s is rare and expressed in less than 1% of the sample. (C) 1994 Wiley- Liss, Inc.